Gastrointestinal · PANCE / PANRE

Colorectal Cancer (CRC)

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

Adenocarcinoma arising from adenomatous or sessile serrated polyps; preventable with screening.

Also known as: colon cancer, rectal cancer, colorectal cancer, CRC

Overview

Malignant neoplasm of the colon or rectum, predominantly adenocarcinoma arising from adenomatous (tubular, tubulovillous, villous) or sessile serrated polyps. Anatomic and biologic differences between right colon, left colon, and rectum influence presentation, treatment, and prognosis.

Epidemiology

Second leading cause of cancer death in the US (~150,000 new cases, ~52,000 deaths annually). 5-year survival ~65% (>90% if localized, ~15% if metastatic). Lifetime risk ~4%. Incidence falling overall due to screening, but rising in adults <50 (early-onset CRC).

Try two board-style Colorectal Cancer questions

Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.

Question 1GastrointestinalMedium
A 45-year-old man undergoes colonoscopy that reveals more than 150 adenomatous polyps carpeting the colon and rectum. His father had colorectal cancer at age 40, and genetic testing confirms an APC gene mutation. Which of the following is the most appropriate management?
  • AObservation with daily aspirin
  • BAnnual colonoscopy with polypectomy
  • CSegmental colectomy with anastomosis
  • DProphylactic total proctocolectomy
Reveal answer & full explanation
Correct answer: D — Prophylactic total proctocolectomy
  • AObservation with daily aspirin
  • BAnnual colonoscopy with polypectomy
  • CSegmental colectomy with anastomosis
  • DProphylactic total proctocolectomy✓

Why Prophylactic total proctocolectomy is correct

  • More than 100 colonic adenomas with a confirmed APC mutation and an affected first-degree relative define familial adenomatous polyposis (FAP), an autosomal dominant syndrome
  • Untreated FAP carries a near-100% lifetime risk of colorectal cancer, often by the fourth decade
  • Prophylactic surgery, typically performed in the late teens to early 20s, is the definitive intervention; the specific operation — restorative proctocolectomy with ileal pouch-anal anastomosis versus total abdominal colectomy with ileorectal anastomosis — is tailored to rectal polyp burden, and with the rectum carpeted in polyps here, only removal of the entire colon and rectum eliminates the at-risk mucosa

Why the others are wrong

  • Observation with daily aspirin - chemoprevention (NSAIDs such as sulindac) may modestly reduce polyp burden but does not remove the near-certain cancer risk (false reassurance)
  • Annual colonoscopy with polypectomy - endoscopic polypectomy cannot keep pace with hundreds of polyps and does not prevent cancer in FAP (right-modality-wrong-disease)
  • Segmental colectomy with anastomosis - resecting one segment leaves the remaining colon and rectum, which this colonoscopy shows are carpeted with adenomas, at near-certain risk of cancer (partial resection of a whole-organ field defect)
Question 2GastrointestinalMedium
A 72-year-old man reports several weeks of rectal bleeding and a change in bowel habits. Digital rectal examination reveals a mass, and colonoscopy shows a 4-cm tumor 6 cm from the anal verge with biopsy confirming adenocarcinoma. Pelvic MRI and staging CT demonstrate a T3N1M0 lesion with no distant metastases. Which of the following is the most appropriate initial treatment?
  • AImmediate low anterior resection
  • BTransanal endoscopic microsurgery
  • CSystemic chemotherapy alone
  • DNeoadjuvant chemoradiotherapy
Reveal answer & full explanation
Correct answer: D — Neoadjuvant chemoradiotherapy
  • AImmediate low anterior resection
  • BTransanal endoscopic microsurgery
  • CSystemic chemotherapy alone
  • DNeoadjuvant chemoradiotherapy✓

Why Neoadjuvant chemoradiotherapy is correct

  • This is locally advanced (stage III, T3N1M0) rectal adenocarcinoma in the mid-rectum (6 cm from the anal verge).
  • Standard of care is neoadjuvant (preoperative) therapy before total mesorectal excision.
  • Neoadjuvant chemoradiotherapy reduces local recurrence from roughly 25% down to 5-8% and can downstage the tumor to permit sphincter preservation.
  • Accepted regimens include long-course chemoradiation (5-FU or capecitabine with 45-54 Gy) or short-course radiotherapy.
  • Total neoadjuvant therapy (delivering all chemotherapy and radiation before surgery) has improved complete-response rates in the RAPIDO and PRODIGE 23 trials.

Why the others are wrong

  • A) Immediate low anterior resection — skips the downstaging step and yields higher local recurrence rates in node-positive disease; it is not the preferred first move for a T3N1 tumor.
  • B) Transanal endoscopic microsurgery — a local-excision technique appropriate only for early, favorable T1 lesions; it does not address nodal disease and is inadequate for a T3N1 tumor.
  • C) Systemic chemotherapy alone — FOLFOX (fluorouracil, leucovorin, oxaliplatin) is the backbone for metastatic colorectal disease and can be part of multimodal therapy, but as a standalone initial treatment it omits the radiation and surgery this localized tumor requires.
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Risk factors

  • Age — median diagnosis ~67 (but rising in younger adults)
  • Personal or family history of CRC or adenomatous polyps
  • Inherited syndromes: Lynch syndrome (HNPCC, MMR mutation), familial adenomatous polyposis (FAP, APC), MUTYH-associated polyposis, Peutz-Jeghers, juvenile polyposis
  • Inflammatory bowel disease (UC > Crohn colitis); risk ~8-10 yr after diagnosis with extensive colitis
  • Primary sclerosing cholangitis (synergistic with IBD)
  • Diet: high red/processed meat, low fiber, low fruits/vegetables
  • Smoking, heavy alcohol
  • Obesity, type 2 diabetes, sedentary lifestyle
  • African American ethnicity (higher incidence and mortality)
  • Prior abdominal radiation

Pathophysiology

Adenoma-carcinoma sequence: normal mucosa → adenoma (APC loss) → carcinoma (KRAS, SMAD4/DPC4, TP53 mutations), taking ~10 years. Alternate serrated pathway: BRAF mutation → CpG island methylator phenotype (CIMP) → sessile serrated lesion → carcinoma. Lynch syndrome: germline mismatch repair (MLH1, MSH2, MSH6, PMS2, EPCAM) defects → microsatellite instability (MSI-H).

Clinical presentation

Symptoms

  • Right-sided (cecum/ascending): occult bleeding → iron-deficiency anemia, fatigue, weight loss; large lumen tolerates mass before obstruction
  • Left-sided (descending/sigmoid): change in stool caliber (narrow/pencil-thin), constipation alternating with diarrhea, hematochezia, obstruction earlier (narrower lumen)
  • Rectal: hematochezia, tenesmus, rectal pain, change in bowel habit
  • Systemic: weight loss, fatigue, anorexia
  • Metastatic: hepatomegaly, jaundice, ascites, bone pain, cough

Signs / physical exam

  • Pallor (anemia)
  • Palpable abdominal mass
  • Hepatomegaly if liver metastases
  • Rectal mass on DRE (most rectal cancers within reach)
  • Lymphadenopathy (Virchow node — rare)
  • Streptococcus gallolyticus (bovis) bacteremia or endocarditis — colonoscopy mandatory

Classic findings

Older adult with iron-deficiency anemia of unclear source (right colon), or change in bowel habit with rectal bleeding (left colon/rectum).

Differential diagnosis

  • Diverticulitis or diverticular disease — LLQ pain, fever; CT distinguishes; colonoscopy 6-8 wk later to exclude CRC
  • Inflammatory bowel disease — Younger patient, chronic bloody diarrhea, extraintestinal manifestations
  • Hemorrhoids / anal fissure — Bright red blood on toilet paper; never assume in older adult without colonoscopy
  • Ischemic colitis — Sudden bloody diarrhea, watershed areas
  • Infectious colitis — Acute onset, exposure, positive stool studies
  • Other GI malignancies (small bowel, anal) — Imaging and biopsy
  • Endometriosis (rectal) — Cyclic rectal bleeding in young women

Diagnostic workup

Diagnostic criteria

Histologic confirmation by colonoscopic biopsy. Staging by AJCC 8th edition TNM. Screening modalities (USPSTF: average-risk adults 45-75): colonoscopy every 10 yr, FIT annually, FIT-DNA (Cologuard) every 3 yr, flexible sigmoidoscopy every 5-10 yr ± FIT annually, CT colonography every 5 yr.

Labs

  • CBC (microcytic anemia)
  • BMP, LFTs (liver metastases)
  • CEA — baseline at diagnosis; surveillance marker (not for screening)
  • Iron studies

Imaging

  • Colonoscopy with biopsy — DIAGNOSTIC; tattoo lesion for surgical localization
  • CT chest/abdomen/pelvis with contrast — staging (M assessment)
  • Rectal cancer: pelvic MRI (T and N staging), endorectal ultrasound (early T staging)
  • PET-CT not routine; selected cases for equivocal metastases
  • Mismatch repair (MMR) or MSI testing on all CRCs — Lynch syndrome screening and immunotherapy candidacy
  • KRAS, NRAS, BRAF, HER2 testing for metastatic disease to guide therapy

Diagnostic algorithm

FeatureRight-sided CRCLeft-sided CRCRectal Cancer
Typical presentationIron-deficiency anemia, occult bleeding, weight lossChange in stool caliber, hematochezia, obstructionHematochezia, tenesmus, change in bowel habit
Lumen sizeWide (late obstruction)Narrower (earlier obstruction)Narrow
Molecular featuresMore MSI-H, BRAF V600E, CIMPMore chromosomal instability, KRASSimilar to left colon
Response to anti-EGFRPoorGood if RAS/RAF wild-typeVariable
Staging imagingCT chest/abd/pelvisCT chest/abd/pelvisPelvic MRI required
Prognosis (stage-matched)Worse for advancedBetterLocal recurrence higher; need TME
Anatomic location influences CRC presentation, molecular biology, treatment response, and prognosis.

Treatment

First-line

  • Multidisciplinary team approach
  • Stage-directed therapy (see by_subtype)
  • Curative-intent surgery is the cornerstone for non-metastatic disease
  • Lifestyle and risk factor counseling

Stage 0 (Tis) / Stage I (T1-T2 N0)

  • Polyp with carcinoma in situ or T1: endoscopic resection with clear margins may suffice if low-risk features
  • Surgical resection (segmental colectomy or low anterior resection / APR for rectum) for higher-risk lesions
  • No adjuvant chemotherapy

Stage II (T3-T4 N0)

  • Surgical resection with adequate lymphadenectomy (≥12 nodes)
  • Adjuvant chemotherapy (5-FU-based ± oxaliplatin — FOLFOX) for high-risk Stage II (T4, perforation, obstruction, <12 nodes harvested, poorly differentiated, lymphovascular invasion, MSI-stable)
  • MSI-H Stage II patients generally do NOT benefit from 5-FU monotherapy

Stage III (any T, N+)

  • Surgical resection
  • Adjuvant FOLFOX or CAPOX × 3-6 months
  • IDEA trial: 3 months may be sufficient for low-risk Stage III (T1-3, N1)

Locally advanced rectal cancer (T3-T4 or N+)

  • Total neoadjuvant therapy (TNT) — induction chemo + chemoradiation OR chemoradiation + consolidation chemo, followed by total mesorectal excision (PRODIGE 23, RAPIDO)
  • Watch-and-wait approach for complete clinical responders (selective)

Stage IV (metastatic)

  • Systemic therapy: FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab (anti-VEGF) or anti-EGFR (cetuximab, panitumumab — only for RAS/RAF wild-type left-sided tumors)
  • Targeted therapy by molecular profile: encorafenib + cetuximab for BRAF V600E; trastuzumab-based for HER2+; pembrolizumab/nivolumab for MSI-H/dMMR
  • Metastasectomy (liver, lung) for oligometastatic disease — potentially curative
  • Palliative resection/diversion/stent for obstructing tumors

Complications

  • Bowel obstruction or perforation
  • Fistula formation
  • Anemia, hemorrhage
  • Metastases — liver (most common), lung, peritoneum, ovary (Krukenberg, although gastric more classic), bone, brain
  • Recurrence after curative resection (~30%)
  • Treatment toxicity: oxaliplatin neuropathy, irinotecan diarrhea, 5-FU mucositis, anti-EGFR rash

PANCE pearls

  • USPSTF lowered CRC screening start age to 45 in 2021 due to rising early-onset disease.
  • Iron-deficiency anemia in postmenopausal women and any man requires evaluation for GI bleeding — colonoscopy + EGD.
  • Streptococcus gallolyticus (S. bovis) bacteremia or endocarditis — colonoscopy is mandatory to exclude colon cancer.
  • Universal MMR/MSI testing on all CRCs at diagnosis identifies Lynch syndrome AND immunotherapy candidates.
  • MSI-H/dMMR metastatic CRC responds dramatically to pembrolizumab (KEYNOTE-177).
  • Anti-EGFR therapy (cetuximab, panitumumab) requires RAS/RAF wild-type AND is most effective in LEFT-sided primaries.
  • Bevacizumab — contraindicated for 28 days post-surgery (poor wound healing, perforation risk).
  • Rectal cancer requires pelvic MRI for staging (T and N) — drives neoadjuvant therapy decisions.
  • Surveillance after curative resection: CEA every 3-6 mo × 5 yr, CT chest/abdomen/pelvis annually × 5 yr, colonoscopy at 1 yr then every 3-5 yr.
  • Lynch syndrome: start colonoscopy at age 20-25 every 1-2 yr; consider screening for endometrial, ovarian, gastric, urothelial cancers.

References

  • USPSTF 2021 — US Preventive Services Task Force. Screening for Colorectal Cancer. JAMA 2021;325:1965-1977
  • NCCN 2024 — NCCN Guidelines Version 5.2024 — Colon Cancer; Rectal Cancer
  • ACG 2021 — Shaukat A et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol 2021;116:458-479
  • KEYNOTE-177 — André T et al. Pembrolizumab in MSI-H–Deficient Mismatch Repair Metastatic Colorectal Cancer. NEJM 2020;383:2207-2218

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Commonly confused with

vs Irritable Bowel Syndrome

Related Gastrointestinal diagnoses

Gastroesophageal Reflux Disease (GERD)Peptic Ulcer Disease (PUD)Helicobacter pylori InfectionEosinophilic Esophagitis (EoE)Esophageal VaricesAchalasiaEsophageal CancerGastric CancerIrritable Bowel Syndrome (IBS)Crohn DiseaseUlcerative Colitis (UC)Diverticulitis and DiverticulosisHemorrhoidsAcute Appendicitis

Differentials & related conditions

Endometriosis

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